It is widely believed that cocaine's ability to reinforce its own administration leads to the sustained, repeated, and heavy use of cocaine. Interventions to treat human cocaine abuse attempt to alter the reward or motivation associated with compulsive use. As models of drug-induced reinforcement, self-administration (SA) paradigms are felt to best approximate naturalistic cocaine abuse. These and other models of dependence have demonstrated that cocaine activates the dopaminergic mesocorticolimbic (MCL) system. At the same time, there is emerging evidence from first preclinical and now human models to suggest that, the hedonic euphoriant effect response to drugs of abuse, although related to activation in striatal, limbic, and paralimbic structures may not be essential to the reinforcing effects of drugs of abuse. Indeed, a number of neuroimaging studies have confirmed that passive cocaine administration in humans activates mesolimbic structures and that this activation is related to behavioral effects. On the other hand, the neurobiological consequences of passive cocaine injections are substantially different from self-administered cocaine. While several animal models of compulsive drug seeking behavior exist, little is known about the neural substrates for the motivation and reinforcement of human cocaine use. This proposal seeks to determine the neuroanatomical sites and neurocognitive mechanisms associated with the reinforcement and reward of cocaine SA in human cocaine dependent individuals using fMRI. Pharmacological and behavioral models will be applied to identify and characterize those neural regions associated with cocaine dose-response, the anticipation of reward associated with SA, as well as determine those regions related to the reinforcement and reward of self-injection in contrast with passive investigator administered cocaine. The characterization of human neural substrates of cocaine reinforcement will lead to a better understanding of the neurobiological pathways underpinning the drive to use cocaine and may help to explain vulnerability to drug abuse. It is expected that such information will be essential to developing more effective clinical treatment strategies by providing insight into the compulsion to abuse this addicting drug.